40 years of adding more fructose to high fructose corn syrup than is safe, through the lens of malabsorption and altered gut health–gateways to chronic disease

Labels do not disclose the excess-free-fructose/unpaired-fructose content in foods/beverages. Objective was to estimate excess-free-fructose intake using USDA loss-adjusted-food-availability (LAFA) data (1970–2019) for high fructose corn syrup (HFCS) and apple juice, major sources of excess-free-fructose, for comparison with malabsorption dosages (~ 5 g-children/ ~ 10 g-adults). Unlike sucrose and equimolar fructose/glucose, unpaired-fructose triggers fructose malabsorption and its health consequences. Daily intakes were calculated for HFCS that is generally-recognized-as-safe/ (55% fructose/45% glucose), and variants (65/35, 60/40) with higher fructose-to-glucose ratios (1.9:1, 1.5:1), as measured by independent laboratories. Estimations include consumer-level-loss (CLL) allowances used before (20%), and after, subjective, retroactively-applied increases (34%), as recommended by corn-refiners (~ 2012). No contributions from crystalline-fructose or agave syrup were included due to lack of LAFA data. High-excess-free-fructose-fruits (apples/pears/watermelons/mangoes) were not included. Eaten in moderation they are less likely to trigger malabsorption. Another objective was to identify potential parallel trends between excess-free-fructose intake and the “unexplained” US asthma epidemic. The fructose/gut-dysbiosis/lung axis is well documented, case-study evidence and epidemiological research link HFCS/apple juice intake with asthma, and unlike gut-dysbiosis/gut-fructosylation, childhood asthma prevalence data spans > 40 years. Results Excess-free-fructose daily intake for individuals consuming HFCS with an average 1.5:1 fructose-to-glucose ratio, ranged from 0.10 g/d in 1970, to 11.3 g/d in 1999, to 6.5 g/d in 2019, and for those consuming HFCS with an average 1.9:1 ratio, intakes ranged from 0.13 g/d to 16.9 g/d (1999), to 9.7 g/d in 2019, based upon estimates with a 20% CLL allowance. Intake exceeded dosages that trigger malabsorption (~ 5 g) around ~ 1980. By the early 1980’s, tripled apple juice intake had added ~ 0.5 g to average-per-capita excess-free-fructose intake. Contributions were higher (~ 3.8 g /4-oz.) for individuals consuming apple juice consistent with a healthy eating pattern (4-oz. children, 8-oz. adults). The “unexplained” childhood asthma epidemic (1980-present) parallels increasing average-per-capita HFCS/apple juice intake trends and reflects epidemiological research findings. Conclusion Displacement of sucrose with HFCS, its ubiquitous presence in the US food-supply, the industry practice of adding more fructose to HFCS than generally-recognized-as-safe, and increased use of apple juice/crystalline fructose/agave syrup in foods/beverages has contributed to unprecedented excess-free-fructose intake levels, fructose malabsorption, gut-dysbiosis and gut-fructosylation (immunogen burden)-gateways to chronic disease.

Mechanisms that drive differences in unpaired fructose absorption capacity are still being explored.Researchers have determined that lower expression of ChREBP, a GLUT5 regulatory gene, likely underlies fructose malabsorption [53,54].In murine research, investigators found that gene deletion of ChREBP, which is expressed in the proximal gut epithelium where carbohydrate digestion and absorption primarily occur and in GLP-1 producing L cells, resulted in impaired expression of glucose, galactose, and fructose transporters, and was accompanied by severe fructose malabsorption syndrome and reduced production of GLP-1 -a hormone that stimulates pancreatic β cells to produce insulin and regulates satiety [54,55].Different alleles and/or variability in ChREBP gene expression may explain differences in excess-freefructose absorption capacity across individuals.Children are more likely to experience fructose malabsorption at lower intakes [14 -16], and limited research shows African Americans have higher fructose malabsorption prevalence than other groups [55].

Study objectives
The first objective of this analysis is to estimate average per capita daily excess-free-fructose intake from HFCS and apple juice, major sources of excess-free-fructose in the American diet, by utilizing USDA loss adjusted food availability (LAFA) data for the years for which data is available (1970 -2019) [62][63][64][65].The US Department of Agriculture (USDA) publishes LAFA data for a broad array of foods including added sweeteners and 100% fruit juices.The USDA "utilizes this data series to estimate average per capita daily intake of foods and sweeteners over time" [62].Source data used in this analysis can be found at https:// www.ers.usda.gov/ data-produ cts/ foodavail abili ty-per-capita-data-system/.
Other growing and increasingly popular sources of excess-free-fructose (EFF), i.e. crystalline fructose (nearly 100% fructose) and agave syrup (70 -90% fructose) [68], are not included in this analysis, as individual LAFA data for these high excess-free-fructose sweeteners are not available/published by the USDA.Consumption trends for high excess-free-fructose fruits (apples, pears, watermelons and mangoes) [3] are also not included herein because when eaten in moderation, these fruits are less likely to trigger fructose malabsorption and its health consequences.
The second objective of this analysis is to assess the impact of adding more fructose to HFCS than is generally-recognized-as-safe [56] on excess-free-fructose consumption trends.Hence, excess-free-fructose average per capita intake estimations are derived for high fructose HFCS variants (65% fructose & 35% glucose; 60% fructose & 40% glucose), as measured in popular beverages, by independent laboratories [1,2].Notably, beverages are the most significant source of HFCS in the American diet -by a wide margin [57].Estimations herein do not include HFCS 42, as it is reasonable to assume, given independent lab results of the HFCS in beverages, that baked goods contain more fructose than assumed, and likely follow a similar practice as measured in beverages.

Methods
Microsoft Excel, and RStudio Version 1.4.1106were used to calculate and plot average per capita excess-freefructose daily intakes from HFCS and apple juice, based upon USDA loss adjusted (retail and consumer level) food availability data, for the time period between 1970 and 2019 [62][63][64].Three intake estimates have been calculated for HFCS.One estimate is based on HFCS with a 1.5:1 fructose-to-glucose ratio (60% fructose / 40% glucose), as measured by independent laboratories in 2014 [2]; the second estimate is based on HFCS with a 1.9:1 fructose-to-glucose ratio (65% fructose / 35% glucose), as measured by independent laboratories in 2010 [1]; and another is based on HFCS with a 1.2:1 fructose-to-glucose ratio (55% fructose / 45% glucose), i.e. the ratio that is generally-recognized-as-safe [56].
For this analysis, retail loss (11%) adjusted, average per capita HFCS availability data have been converted to grams per day for each year (g/d/y) herein (1970 -2019) (lb./yr * 453.59)/365) (Tables 1, 2 and 3).Annual retail loss adjusted data (g/d/y) were then updated to include consumer level loss (CLL) allowances which account for "cooking loss and uneaten food" [64,65].However, due to controversy surrounding the accuracy of USDA's consumer level loss allowance for HFCS [63][64][65], three intake estimates have been calculated for each HFCS variant.One estimate includes a 15% consumer level loss factor, as recommended by independent researchers tasked with improving CLL accuracy (2012) [63]; another estimate includes the historically used CLL factor (20%); and the third estimate includes the newly adopted (2012), retroactively applied CLL factor (34%), as recommended for HFCS by US corn refiners -a biased group [63][64][65].
The following formulae define the three steps used to derive excess-free-fructose daily intake from HFCS availability data: Step 1 -Subtract the consumer level loss allowance (15% or 20% or 34%) from retail-loss-adjusted data.
The same approach was used to calculate excess-freefructose daily intake from average per capita LAFA data for apple juice.The fructose to glucose ratio (~ 2.1:1) in apple juice (68/32) was obtained from the US National Nutrients Database (NDB) [3] (No. 09400).100 g of apple juice contains 5.7 g of fructose + 2.6 g of glucose (1 oz.contains 1.8 g fructose and 0.8 g glucose) [3].Estimations include USDA's retail (11%) and consumer level (10%) loss allowances for apple juice.Results are depicted in Fig. 1, plots D -F.
Figures 2 and 3, plots D-F, show contributions to excess-free-fructose intake from half a cup (~ 4 g) and a cup of apple juice (~ 8 g), respectively, i.e. servings consistent with a healthy eating pattern for children and adults [72], as defined in the 2020-2025 Dietary Guidelines for Americans. Figures

Results
It is evident, from Figs. 1, 2 and 3, that the ubiquitous presence of HFCS in the US food supply has exposed consumers to more excess-free-fructose than at any other time in US history; that average per capita excess-freefructose daily intakes from HFCS, at higher fructose-toglucose ratios than are considered safe, exceeded dosages associated with fructose malabsorption (~ 5 g) beginning in the early 1980's, as based upon estimates with a ≤ 20% consumer level loss factor (Figs. 1, 2 and 3 and Tables 1, 2 and 3); and although HFCS intake has dropped from its peak in 1999, average per capita excess-free-fructose daily dosages, from HFCS, continue to exceed pediatric (~ 5 g), and approach adult dosages (~ 10 g) associated with fructose malabsorption, and its health consequences.Daily intakes are understated because this analysis does not include unpaired fructose from agave syrup and crystalline fructose -high excess-free-fructose sweeteners.It is also evident that differences in HFCS fructose-to-glucose ratios and consumer level loss factors  and 3).Excess-free-fructose daily intake for individuals consuming HFCS with an average 1.5:1 fructose-to-glucose ratio, ranged from 0.10 g/d in 1970, to 11.3 g/d in 1999, to 6.5 g/d in 2019, and for individuals consuming HFCS with an average 1.9:1 ratio, intakes ranged from 0.13 g/d in 1970, to 16.9 g/d at peak consumption (1999), to 9.7 g/d in 2019, based upon estimates that included a 20% consumer level loss allowance.Importantly, 10% of adults are fructose malabsorption positive after a 12 g excessfree-fructose dosage, and contributions to daily dosages from crystalline fructose and agave syrup-sweeteners with high concentrations of unpaired fructose-are not included in this analysis, nor are contributions from apple juice.
Contributions to daily excess-free-fructose intake, from average per capita loss-adjusted apple juice intake, rose steadily from ~ 0.2 g/d (1970), to ~ 0.5 g/d (1984), to ~ 0.7 g/d at peak consumption (2007), and back down to ~ 0.5 g/d in 2019 (Table 4).By the early 1980's, the tripling of apple juice intake, had added about a half a gram to average per capita excess-free-fructose daily intake (Fig. 1, plots D-F).
By 1980, daily average per capita excess-free-fructose intake from HFCS, when combined with a half cup of apple juice (~ 3.8 g of excess-free-fructose), exceeded dosages associated with pediatric fructose malabsorption (~ 5 g for a toddler weighing 10 kg (22 lbs.), i.e. 0.5 g/ kg of body weight), across all HFCS variants, including the HFCS variant that is generally-recognized-as-safe (HFCS 55/45) (Fig. 2, plots D-F and Table 4), irrespective of which consumer level loss allowance was used, including the subjective, retroactively applied increase to 34%.
Throughout the period for which data is available (1970 -2019), excess-free-fructose dosages g/d/y, from average per capita HFCS intake, remained below the pediatric fructose-malabsorption-associated-dosage (~ 5 g/d), only for the HFCS variant that is generally-recognized-as-safe (55/45), and only when the consumer level loss allowance was 34%, as recommended by corn refiners (Figs. 1, 2 and 3).Dosages reached ~ 4.7 g/d at peak HFCS consumption (1999).Hence, the retroactively applied increase in the consumer level loss allowance (~ 2012) for HFCS, from 20 to 34%, had a material effect on excess-free-fructose daily dosage estimates.The retroactively applied (1970's) increase to 34% (~ 2012) appears self-serving.
It is evident (Figs. 4, 5, 6 and 7) that increasing intakes of apple juice and HFCS, but not orange juice (Fig. 5), parallel increases in pediatric asthma prevalence, an age group with higher fructose malabsorption vulnerability / prevalence at lower excess-free-fructose intake than other groups.

Discussion
Results herein show that the practice of adding more fructose to HFCS, than is generally-recognized-as-safe [56], has a compounding effect on excess-free-fructose dosages.It is evident that by the early 1980's, daily average per capita excess-free-fructose contributions, from HFCS, exceeded dosages associated with pediatric fructose malabsorption (~ 5 g) [15,16] and its broader health consequences .For individuals consuming HFCS at average or above average consumption levels, that contained higher than generally-recognized-assafe fructose-to-glucose ratios [56], this milestone was reached between 1980 -1982, a period coincident with the advent of the "unexplained" US asthma epidemic  [73-78], and with increases in heart/kidney disease mortality racial disparities [79][80][81][82][83][84], and that is before considering contributions from apple juice.
There are no known genetic mutations associated with fructose malabsorption [85] which would not be a problem if not for the advent and widespread use of sweeteners with high fructose-to-glucose ratios (HFCS [1,2], crystalline fructose (100% fructose), agave syrup (70%-90% fructose) [68,86] and apple powder [3]).Excess-free-fructose average per capita intake estimates herein are therefore understated, as these additional sources of excess-free-fructose (crystalline fructose, agave syrup, and apple powder) have not been accounted for in this analysis.
Notably, the excess-free-fructose content in a 12 oz.can of cola with 39 g of HFCS is 3.9 g (21.45 -17.55 = 3.9 g) when the fructose/glucose percentages are 55/45, i.e. the GRAS 1.  1.5:1 ratio), and jumps to11.6 g, when the HFCS variant is 65/35 (~ 25.3 g -13.7 g = 11.6 g), i.e. the 1.9:1 ratio.From a national nutrition and health policy perspective, recommendations to reduce sugar sweetened beverage (SSB) intake are inadequate to address unwitting exposures, as high fructose-to-glucose sweeteners (HFCS [1,2], crystalline fructose, apple powder [3], apple juice [3], and agave syrup [68,86]) are ubiquitous in the US food supply.The practice of adding more fructose to HFCS, than is generally-recognized-as-safe, as reported by the University of Southern California's Keck School of Medicine [1,2], is likely not limited to beverages.
Nutrition labels should provide details of total fructose content, and more importantly, of the excess-free-fructose content in foods and beverages.This is consistent with recommendations by researchers at the Keck School of Medicine [1,2].Warnings are warranted when foods contain excess-free-fructose.Not only do nutrition labels not provide information of the fructose-to-glucose ratio in added sweeteners or the excess-free-fructose / unpaired fructose content, even if they did, independent oversight is needed to ensure compliance with safety standards.It is noteworthy that 100% crystalline fructose is promoted as a low glycemic alternative to table sugar, and is available for purchase in US grocery stores, but is void of malabsorption warnings [87].Recommendations to limit added sugar intake as a means of improving diet quality / health are inadequate and fail to provide the consumer protections that are needed.It is worth noting that prior to an undisclosed settlement agreement, between the US Sugar Association and US corn refiners, HFCS was heavily promoted as "just like sugar" [88,89].This messaging likely slowed research of excessfree-fructose induced consequences of fructose malabsorption beyond gas, bloating and interference with nutrient absorption-research which continues to lack momentum.
Asthma is characterized by cough not associated with a cold or flu, narrowing of the airways, wheeze, dyspnea / difficulty breathing, airway mucus hypersecretion that leads to infection and inflammation by providing an environment for microbial growth [90][91][92].Gut and lung dysbiosis [25] and gastroesophageal reflux disease (GERD) are comorbidities of asthma [92].Dysbiosis and subsequent dysregulation of microbiota-related immunological processes affect the onset of the disease, its clinical characteristics, and responses to treatment [25].Uncontrolled asthma contributes to increased absenteeism and reduced quality of life.Emergency symptoms include bluish color to the lips and face, rapid pulse, severe anxiety   due to shortness of breath, difficulty speaking and confusion.Breathing can temporarily stop and can lead to heightened risk of death [90][91][92].

Conclusion
The displacement of sucrose with HFCS, its ubiquitous presence in the US food supply, and the industry practice of adding more fructose to HFCS than is generally-recognized-as-safe, combined with the increased use of apple juice as a sweetener in foods and beverages, and growing use of crystalline fructose, agave syrup (70-90% fructose) and apple powder, have all contributed to unprecedented excess-free-fructose daily intake levels.Dosages have exceeded and continue to exceed levels that trigger fructose malabsorption (~ 5 g-10 g)-a condition with far reaching consequences.Excess-free-fructose promotes gut formation of asthma provoking, proinflammatory advanced glycation end-products (FruAGE) and causes gut dysbiosis -a disease associated with a growing list of chronic diseases including asthma, COPD, autoimmune disease, IBD, IBS, CVD, NAFLD, CKD, and cardiometabolic and mental health disorders.

Fig. 5 Fig. 6
Fig. 5 US Childhood Asthma Prevalence and Average Per Capita Orange Juice Intake -1980 to 2019

Fig. 7
Fig. 7 US Childhood Asthma Prevalence and Average per Capita High Fructose Corn Syrup and Apple Juice Intake -1980 to 2019

Table 1
Excess-free-fructose intake (g/d) from HFCS that is 55% fructose extrapolated from average per capita loss adjusted food availability (LAFA) data a

Year Unadjusted per capita availability of HFCS in lb/y a Per capita availability of HFCS (lbs/y) after retail loss of 11% a Per capita availability of HFCS (g/d) after retail loss
4, 5, 6 and 7 depict combined plots of childhood asthma prevalence and average per capita intake trends for apple juice, orange juice, HFCS, and HFCS + apple juice(1980 -2019).Orange juice intakes are based upon USDA Loss Adjusted Food Availability data, which

Table 2
Excess-free-fructose intake (g/d) from HFCS that is 60% fructose, as extrapolated from average per capita loss adjusted food availability (LAFA) data a

Table 3
Excess-free-fructose intake (g/d) from HFCS that is 65% fructose, as extrapolated from average per capita loss adjusted food availability (LAFA) data a

Table 3
(continued) a Source is the U.S. Department of Agriculture, Economic Research Service (ERS).The ERS Food Availability (Per Capita) Data System.Economic Research Service Home

Table 4
Excess-free-fructose intake (g/d) from apple juice, as extrapolated from average per capita loss adjusted food availability (LAFA) data b

b Per capita availability of apple juice (lb/y) after 6% retail loss allowance b
[29]g of fructose and 0.82 g of glucose/ounce of apple juice or 5.73 g of fructose and 2.63 g of glucose/100 g of apple juice[29]Department of Agriculture, Economic Research Service.2012.The ERS Food Availability (Per Capita) Data System.Economic Research Service Home Page, https:// www.ers.usda.gov/ data-produ cts/ food-avail abili typer-capita-data-system/ https:// www.ers.usda.gov/ data-produ cts/ food-avail abili ty-per-capita-data-system/ food-avail abili ty-docum entat ion/ a There are 1b U.S.